Diabetic complications including heart disease, stroke, nephropathy, neuropathy, retinopathy, infectious diseases, sexual dysfunction, bone loss and dental diseases, are highly significant health problems and the underlying molecular pathways, likely modulated by hyperglycemia, remain poorly understood. In this study, we will use a combination of genetics and systems biology to identify molecular pathways that contribute to diabetic nephropathy and cardiovascular complications. We will use a novel mouse genome wide association strategy across a hybrid mouse diversity panel (HMDP). The HMDP consists of ~100 common inbred and recombinant inbred (RI) strains which have been either entirely sequenced or densely genotyped. We have already demonstrated the power of this approach to detect and finely map associations for complex traits, to suggest pathways associated with the traits and to rapidly identify the underlying gene variations. Because the HMDP is renewable (strains are commercially available), the genotyping does not need to be repeated and the panel can be assayed for multiple phenotypes providing cumulative biological insights. To identify the genetic factors contributing to diabetic complications, we will generate diabetic and euglycemic mice by crossing each strain of the HMDP to Akita/+ mice. The mouse Akita mutation (Ins-2 gene) induces the unfolded protein response and apoptosis in pancreatic islet beta cells, even in heterozygous F1 animals. Our early studies have shown that diabetic hyperglycemia severity is comparable across F1 animals with diverse genetic backgrounds. By contrast, different F1 strains exhibit varying responses to diabetes with respect to complications, including nephropathy, heart function, vascular calcification, and atherosclerosis. We will take advantage of current high-throughput transcriptomic and metabolomic assays, combined with dense genotype information and recent advances in computational methods, to identify candidate genes responsible for these diabetic complications. The candidate genes and pathways will be validated in genetically modified mice or in cell-based systems. We have recently shown that hyperglycemia induces bone morphogenetic protein (BMP) signaling in cultured human endothelial cells and in the blood vessels of Akita mice. This pathway clearly contributes to diabetes-mediated vascular calcification and we will test the hypothesis that BMP signaling is also involved in other macro- and micro-vascular complications of diabetes. The team of investigators has strong expertise in the characterization of multiple diabetic complications as well as a proven record in the analysis of complex traits in mice. To our knowledge, this novel project is the first large scale integrated genetics study to identify and finely map hyperglycemia modulated molecular pathways that determine susceptibility to the complications of diabetes. PUBLIC HEALTH RELEVANCE: Over 20 million people in the U.S. suffer from diabetes mellitus. And, while the risk for heart disease, stroke, nephropathy, neuropathy, retinopathy, infectious diseases, sexual dysfunction, and dental diseases are markedly increased in diabetic individuals, the underlying molecular pathways for these diabetic complications remain poorly understood. The goal of this project, identifying molecular mechanisms responsible for diabetes accelerated diseases, remains a critical goal in the drive to develop better treatments and preventative measures.